Tuberculosis, due to infection with Mycobacterium tuberculosis, is the most prevalent infection globally, with up to 40% of the world's population (1.8 billion people) infected. The vast majority of these infections are latent (chronically persistent in the setting of established antimycobacterial immunity), a stage which is critically dependent upon CD4+ lymphocytes. Several recognized factors result in the breakdown of established immunity, leading to reactivation of the infection and overt disease, including concurrent HIV infection or adverse socioeconomic conditions. The latter includes alcohol abuse. Alcohol adversely impacts the immune system, including lymphocytes. In murine models, vaccination with M. bovis Bacille Calmette-Guerin (BCG) followed by lung infection with M. tuberculosis models latent infection (by resulting in chronic persistent infection). Based on our work in the prior funding period, we hypothesize that alcohol consumption impairs M. bovis BCG-induced protection against pulmonary infection with M. tuberculosis in mice by disrupting effector CD4+ Th1 lymphocyte responses that are necessary to control the proliferation of M. tuberculosis. This will be tested in a murine model of chronic alcohol consumption and pulmonary infection with virulent M. tuberculosis after immunization with BCG. The Specific Aims are: Specific Aim 1. To test the hypothesis that alcohol consumption by mice will disrupt M. bovis BCG-induced CD4+ Th1 effector lymphocyte (vs. cognate) immunity against pulmonary infection with M. tuberculosis. Specific Aim 2. To test the hypothesis that alcohol-induced disruption of M. bovis BCG induced immunity against pulmonary infection with M. tuberculosis is due to impaired expansion, recruitment, and/or function of CD4+ Th1 lymphocytes. Specific Aim 3. To test the concept that alcohol-induced defects in BCG-induced protection against pulmonary challenge with M. tuberculosis can be reconstituted via immunomodulation (i.e., cytokine gene therapy). The goal of the proposed project is to elucidate the specific effects of alcohol consumption on the breakdown of established antimycobacterial immunity, and to develop strategies to prevent these events